The need for a better understanding of the correlates of protective immunity remains urgent, and will require a comprehensive analysis of the complex virologic and immunologic events associated with infection by the human immunodeficiency virus type 1 (HIV-1). A detailed analysis of these factors in infected long-term non-progressing persons and exposed yet uninfected persons offer the opportunity to identify the protective host defenses which are most relevant for an effective vaccine. The objective of the proposed Program Project is to provide, through systematic patient sampling and intensive, detailed and interrelated laboratory studies, the correlates of immune protection. It is the premise of this proposal that possible correlates of protective immunity against HIV-1 can be determined by extensive, indept evaluation of HIV-1-specific humoral and cellular immune responses and host cellular factors of natural history cohort study subjects. Important correlative data will be provided by detailed characterization of the virus genotype and biological and serological phenotype. The overall goal of this Program Project is to determine: (1) the virological and immunological basis of virus transmission, or lack thereof, in individuals apparently exposed to, but not infected by HIV-1; and (2) the virological and immunological basis of slow verses rapid progression in subjects enrolled in natural history cohorts. The coordinated studies proposed herein will provide vital information and reagents needed to facilitate the development of an effective HIV-1 vaccine.